Targeted at learning about inflammatory eye diseases, this project focused in FY 1999 on mechanisms that determine susceptibility to autoimmune-mediated and other Inflammatory eye diseases, as well as new experimental approaches for modulation of ocular inflammation. Noteworthy results include the following: (1) Immunohistochemical analysis of rodent thymi revealed the presence of cells that express ocular- specific antigens, S-antigen (arrestin), interphotoreceptor retinoid-binding protein (IRBP) or alpha-crystallin. These cells localize mainly in the thymic medulla and typically exhibit the morphology of dendritic cells. It is assumed that the ocular antigens expressed by these thymic cells are those detected in thymic extracts in our previous study (J. Immunol., 159:3109, 1997). Furthermore, in accord with the previous observation, an inverse correlation was found among different mouse strains between the number of cells expressing retinal antigens and susceptibility to experimental autoimmune uveoretinitis (EAU). These data thus support the notion that cells expressing ocular antigens are responsible for elimination of lymphocyte clones capable of initiating autoimmunity toward eye antigens. (2) Little is known about the pathogenesis of endotoxin-induced uveitis (EIU), that serves as an animal model for anterior uveitis in humans. In a previous study (Invest. Ophthal. Vis. Sci. 34:2911, 1993) we showed that, unexpectedly, inhibition of the pro-inflammatory cytokine tumor necrosis factor alpha (TNF-alpha) resulted in enhanced severity of EIU in mice. This phenomenon was further investigated in FY 1999 by testing the effects of a compound that reduces the blood level of TNF. Vasoactive intestinal peptide (VIP) reduced the levels of TNF-alpha in mouse blood and significantly enhanced the ocular inflammatory reaction in mice treated with endotoxin. (3) Two new approaches were tested for suppression of EAU: (I) Treatment with copolymer 1 (Cop 1). Cop 1, a synthetic random copolymer, inhibits experimental allergic encephalomyelitis and reduces symptoms of multiple sclerosis. Administration of Cop 1 significantly inhibited the development of EAU in mice. In addition, Cop 1- treated mice exhibited reduced cellular response against the uveitogenic antigen (IRBP). The data suggest that Cop 1 inhibits the pathogenic immune response by competing with IRBP for the antigen presenting cells. (ii) Treatment with a uveitogenic peptide conjugated to rat immunoglobulin (Ig), or to antibody against Ig. Development of EAU induced in rats by IRBP peptide 1179-1191 was inhibited by treatment with this peptide, conjugated to rat Ig or to antibody against rat Ig. Moreover, treatment with the conjugates also effectively inhibited EAU induced by adoptive transfer of lymphocytes sensitized against peptide 1179-1191, thus showing that the conjugates are capable of inhibiting both the afferent and efferent limbs of the immunopathogenic process. Analysis of antibody isotypes in the experimental animals revealed that treatment with the conjugates diverted the T-cell response against peptide 1179-1191 from the pathogenic type 1 to the protective type 2.